The long term objectives of the proposed research are to determine whether adenosine and lipoxygenase metabolites of arachidonic acid play a role in local regulation of fetal blood flow in the human term placenta, and whether prostanoids and angiotensin contribute to the local regulation. The in vitro dual-perfused placental cotyledon preparation from human term placentas will be used to investigate effects of lipoxygenase metabolites such as lipoxins and leukotrienes on the resistance of the fetoplacental vasculature, and on placental production of these metabolites, prostanoids and adenosine during hypoxic fetoplacental vasoconstriction, and in response to ischemia; effects of hypoxia on conversion of angiotensin I to angiotensin II by the fetoplacental vascular bed will be investigated. Vasoconstriction may be an important compensatory response of the fetoplacental vasculature to maternal hypoxia. The possibility that placental production of lipoxygenase metabolites, prostanoids and adenosine may influence the uteroplacental circulation will be investigated by measuring their release, and that of renin, into the maternal circuit of dual-perfused cotyledons in response to hypoxic stimulus. Assay techniques will include high pressure liquid chromatography and radioimmunoassay. Changes in adenine nucleotide profiles of placental cotyledons and concomitant production of adenosine will be correlated with degree of hypoxic stimulus and with ischemia. Modulation by hypoxia of the pathways of placental arachidonate metabolism to prostanoids and lipoxygenase metabolites will be determined in placental tissue labeled with (14C)-arachidonate. Levels of adenosine, inosine and hypoxanthine (purines) in lobules of freshly delivered human term placentas will be measured by high pressure liquid chromatography and placental adenosine and purine content of normal term placentas will be correlated with duration of labor, and with the adenosine and purine content in preeclamptic placentas, and placentas associated with acute or chronic fetal distress, e.g. hypertension. It is expected that this integrated approach of assessing both vascular and biochemical responses of the placenta will lead to a better understanding of the control of feto-placental blood flow in normal and abnormal conditions, and provide information pertinent to understanding preeclampsia.